Abstract

Mycoepoxydiene (MED) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp. HLY-1, which is associated with mangroves; however, the mechanism of action of MED remains unknown. Here, we report the molecular mechanisms of apoptosis activation and growth inhibition induced by MED in MCF-7 cells. The present results show that MED induces DNA damage through the production of reactive oxygen species (ROS), which resulted in the phosphorylation of H2AX and the activation of the Ataxia telangiectasia mutated kinase (ATM) and p53 signaling pathways. In addition, MED increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27, which eventually resulted in the inhibition of TNF-α-induced NF-κB transactivation. Therefore, we conclude that MED inhibits MCF-7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF-κB to disrupt cell proliferation. Because small molecules having both of these effects are rare, further exploration of MED as an antitumor lead compound is needed.

Links

Publisher Full Text

Authors

Wang J, Zhao B, Yi Y, Zhang W, Wu X, Zhang L, Shen Y

Institution

State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, PR China.

Source

Biochemical pharmacology 84:7 2012 Oct 1 pg 891-9

MeSH

Antineoplastic Agents
Apoptosis
Ascomycota
Bridged Compounds
Cell Cycle
Cell Division
Cell Line, Tumor
DNA Damage
Gene Expression Regulation
HSP27 Heat-Shock Proteins
Humans
NF-kappa B
Pyrones
Reactive Oxygen Species
Tumor Necrosis Factor-alpha
Tumor Suppressor Protein p53

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22796259